1. Field of the Invention
The present invention relates generally to the field of drug delivery systems. In particular, the present invention relates to osmotic pump systems, devices, kits and associated methods for shortening the time interval between implantation of the osmotic pump system and delivery of a pharmaceutical agent to the patient. The present invention also relates to osmotic implantable systems and methods for delivering multiple drugs simultaneously (and/or sequentially), implantable osmotic systems having redundant pumps, as well as systems, methods and kits for delivering mixtures of drugs and/or potentiating drugs.
2. Description of the Related Art
Since the beginning of modern medicine, drugs have been administered orally. Patients have taken pills as recommended by their physician. The pills must pass through the digestive system and then the liver before they reach their intended delivery site (e.g., the vascular system). The actions of the digestive tract and the liver often reduce the efficacy of medication; furthermore, medications delivered systemically sometimes cause undesirable side effects. Over the course of the past few decades, drug delivery technology and administration has evolved from oral delivery to site-specific delivery. In addition to the oral route of administration, drugs are also routinely administered via the vascular system (intravenous or IV). Intravenous drug delivery has the advantage of bypassing the acidic and enzymatic action of the digestive system. Unfortunately, IV administration requires the use of a percutaneous catheter or needle to deliver the drug to the vein. The percutaneous site requires extra cleanliness and maintenance to minimize the risk of infection. Infection is such a significant risk that IV administration is often limited to a number of weeks, at most. In addition, the patient must wear an external pump connected to the percutaneous catheter.
The next step in the evolution of drug delivery was the implanted pump. The implanted pump is a device that is completely implanted under the skin of a patient, thereby negating the need for a percutaneous catheter. These implanted pumps provide the patient with a drug at a constant or a programmed delivery rate. Constant rate or programmable rate pumps are based on either phase-change or peristaltic technology. When a constant, unchanging delivery rate is required, a constant-rate pump is well suited for long-term implanted drug delivery. If changes to the infusion rate are expected, a programmable pump may be used in place of the constant rate pump. Fully implanted constant rate and programmable rate infusion pumps have been sold in the United States for human use since the late 1970s and early 1980s, respectively. Two problems associated with such 1970s and 1980s vintage constant rate and programmable rate infusion pumps relate to their size and their cost. Current implantable constant rate and programmable pumps are about the size and shape of hockey pucks, and they typically are sold to the hospital for $5,000-$9,000. The current implantable pumps must be implanted in the Operating Room under general anesthesia, which further increases costs, as well as the risk, and discomfort to the patient. The size and cost of such pumps has proven to be a substantial barrier to their use, and they are rarely used to deliver medication. An added drawback of phase-change and peristaltic pumps is that they must be refilled with drug every 3-8 weeks. Refills constitute an added burden to the caregiver, and add further costs to an already overburdened healthcare system. The burden associated with such refills, therefore, further limits the use of phase-change and peristaltic pumps.
In the 1970s, a new approach toward implanted pump design was commercialized for animal use only. The driving force of the pumps based upon this new approach utilized the principle of osmosis. Osmotic pumps may be much smaller than other constant rate or programmable pumps, because their infusion rate can be very low. An example of such a pump is described listed in U.S. Pat. No. 5,728,396, the disclosure of which is hereby incorporated herein in its entirety. This patent discloses an implantable osmotic pump that achieves a sustained delivery of leuprolide. The pump includes an impermeable reservoir that is divided into a water-swellable agent chamber and a drug chamber. Fluid from the body is imbibed through a semipermeable plug into the water-swellable agent chamber and the drug is released through a diffusion outlet at a substantially constant rate.
However, osmotic pumps of this type are configured to deliver a single drug (or a single combination of drugs) at a time and at a single delivery rate. Should the patient develop a tolerance to the drug and require an increased dose to alleviate pain, for example, such a single drug/single dose pump is unable to provide the needed relief. In such a case, the physician may need to supplement the drug delivered by the implanted pump with another drug or more of the same drug, delivered via an intravenous route, for example. This, however, defeats the purpose of the implanted pump, namely to provide a self-contained drug delivery system that operates with little or no discomfort to the patient. What are needed, therefore, are novel implantable pumps and pump systems able to deliver a drug at more than a single rate.
There may be instances, moreover, when a simple increased dose of the same drug is ineffective to achieve the desired therapeutic result. In such cases, the administration of another drug may be indicated, whether in place of or in addition to the originally delivered drug. Conventional osmotic pumps, however, are single drug or single drug combination devices: they can only infuse a single drug or a single combination of drugs at a time. To administer another drug, several alternatives are available, all of which involve significant discomfort to the patient. One such alternative is to administer the other drug intravenously while the osmotic pump remains implanted. Another alternative is to surgically remove the originally implanted drug and to implant another osmotic pump configured to deliver the other drug. These alternatives are also the only ones available when the implanted osmotic pump fails to function or runs out of drug, whether at the end of its useful life or whether the pump fails unexpectedly. What are also needed, therefore, are implantable osmotic pump systems configured for the selective delivery of more than one drug or more than one drug combination, at individually selectable rates. Also needed are implantable osmotic pump systems that include a built-in backup drug delivery system, the backup system being effective to continue the delivery of the drug when the primary delivery system reaches the end of its useful life or fails unexpectedly.
It is an object of the present invention, therefore, to provide novel implantable pumps and pump systems adapted to deliver a drug at more than a single rate. It is another object of the present invention to provide implantable osmotic pump systems configured for the selective delivery of more than one drug or more than one drug combination, at individually selectable rates. A still further object of the present invention is to provide osmotic pump systems that include a built-in backup drug delivery system, the backup system being effective to continue the delivery of the drug when the primary delivery system reaches the end of its useful life or fails unexpectedly.
In accordance with the above-described objects and those that will be mentioned and will become apparent below, an implantable osmotic pump system, according to an embodiment of the present invention includes a first osmotic pump including a first semipermeable membrane; a second osmotic pump including a second semipermeable membrane, and a single catheter attached to both the first and the second osmotic pumps.
The catheter may include a first lumen and a second lumen, the first lumen being connected to the first osmotic pump and the second lumen being connected to the second pump. Alternatively, the catheter may include a single lumen with two side arms, one of the two side arms being attached to the first pump and the other of the two side arms being attached to the second pump, each of two side arms including an internal lumen that feeds into the single lumen. The second semipermeable membrane may be sealed by an impermeable membrane. The impermeable membrane may be disposed over and away from semipermeable membrane so as to define a fluid tight compartment therewith. The impermeable membrane may be adapted to be punctured with a lancet when the pump system is implanted in a patient and may include, for example, titanium, stainless steel, a polymer such as polyethylene, polyethylene terephthalate (PET) or PETG and/or any biologically inert material adapted to be breached by a lancet or like device.
The first and second pumps may be preloaded with one or more pharmaceutical agents. The first pump may be preloaded with a first pharmaceutical agent at a first therapeutically effective concentration and the second pump may be preloaded with a second pharmaceutical agent at a second therapeutically effective concentration. The first pharmaceutical agent may be the same pharmaceutical agent as the second pharmaceutical agent or a different agent. Likewise, the first concentration may be at the same or different as the second concentration. The first pharmaceutical agent may potentiate a therapeutic property of the second pharmaceutical agent. For example, the first pharmaceutical agent may be an opioid and the second pharmaceutical agent may include a drug that potentiates an analgesic property of the first pharmaceutical agent, such as the alpha 2-adrenoreceptor agonist Clonidine.
The first pump may be preloaded with a first opioid and the first pump may be adapted to infuse the first opioid at a first therapeutically effective range of concentration. Likewise, the second pump may be preloaded with a second opioid and the second pump may be adapted to infuse the second opioid at a second therapeutically effective range of concentration after the semipermeable membrane is breached. The first opioid may include Fentanyl and/or Sufentanil and the second opioid may include Fentanyl and/or Sufentanil. The first opioid may be the same opioid as the second opioid and the second pump may be adapted to infuse the second opioid at the first therapeutically effective range when the first pump is out of the first opioid, upon breaching the impermeable membrane.
The present invention may also be viewed as a kit, comprising a first osmotic pump including a first semipermeable membrane; a second osmotic pump including a second semipermeable membrane, and a single catheter adapted to attach to both the first and the second osmotic pumps.
The second semipermeable membrane may be sealed by an impermeable membrane. The impermeable membrane may be disposed over and away from the one of the first and second semipermeable membrane so as to define a fluid tight compartment therewith. A lancet configured to breach the impermeable membrane may also be included in the kit. The first and second osmotic pumps may be preloaded with first and second pharmaceutical agent(s), respectively. For example, the first pharmaceutical agent may include Fentanyl and the second pharmaceutical agent includes Sufentanil. Alternatively, the first pharmaceutical agent may include Sufentanil and the second pharmaceutical agent may include Clonidine.
The present invention is also a drug delivery method, comprising the steps of infusing a first drug at a first therapeutically effective range of concentration from a first implanted osmotic pump; infusing a second drug at a second therapeutically effective range of concentration from a second implanted osmotic pump; preventing the first and second drugs from mixing until both the first and second drugs reach an intended delivery site.
The preventing step may be carried out by attaching a catheter having a first and a second lumen to the first and second osmotic pumps, the first lumen being in fluid communication with the first osmotic pump and the second lumen being in fluid communication with the second osmotic pump, a free end of the catheter being disposed at the intended delivery site. The first and second drugs may be therapeutically effective for pain therapy, hormone therapy, gene therapy, angiogenic therapy, anti-tumor therapy, chemotherapy and/or other pharmaceutical therapies.
According to another aspect thereof, the present invention is an implantable osmotic pump system, comprising: a first osmotic pump, including a first semipermeable membrane; a first impermeable membrane initially sealing the first semipermeable membrane; a second semipermeable membrane and a second impermeable membrane initially sealing the second semipermeable membrane, and a second osmotic pump, including a third semipermeable membrane; a third impermeable membrane initially sealing the third semipermeable membrane; a fourth semipermeable membrane and a fourth impermeable membrane initially sealing the fourth semipermeable membrane.
Each of the first and second pumps may include a proximal end, a distal end and a sidewall. One or both of the first and second initially sealed semipermeable membranes may be fitted to a side wall of the first pump and one or both of the third and fourth initially sealed semipermeable membranes may be fitted to a side wall of the second pump. Each of the first and second pumps may include a proximal and a distal end, and a catheter may be attached to the distal end of the first pump and to the distal end of the second pump. Each of the first to fourth impermeable membranes may be disposed over and away from the first to fourth semipermeable membranes, respectively, so as to define a first to fourth fluid tight compartment therewith, respectively. Each of the first to fourth impermeable membranes may be adapted to be punctured with a lancet when the pump system is implanted in a patient. The impermeable membranes may include titanium, stainless steel, platinum-iridium, polyethylene, PET and PETG and/or any biologically inert material that is impermeable to water. The first and second pumps may be preloaded with pharmaceutical agent(s). For example, the first pump may be adapted to deliver a dose of Fentanyl of about 10 to about 300 milligrams per day and the second pump may be adapted to deliver a dose of Sufentanil of about 1 to about 25 micrograms per day. Alternately, the first pump may be adapted to deliver a dose of Sufentanil of about 1 to about 25 micrograms per day and the second pump may be adapted to deliver a dose of Clonidine of about 25 to about 150 micrograms per day.
This pump system may be used by carrying out steps of breaching the first impermeable membrane; implanting the pump system into a patient to start infusion of the first pharmaceutical agent at a first therapeutically effective dose; breaching the second impermeable membrane to start infusion of the first pharmaceutical agent at a second therapeutically effective dose when the patient develops a tolerance to the first dose; breaching the third impermeable membrane to start infusion of the second pharmaceutical agent at a third therapeutically effective dose when the patient develops a tolerance to the first pharmaceutical agent, and breaching the fourth impermeable membrane to start infusion of the second pharmaceutical agent at a fourth therapeutically effective dose when the patient develops a tolerance to the third dose. The breaching steps may be carried out by puncturing the first to fourth impermeable membranes with a lancet.
According to still another embodiment, an implantable osmotic pump, comprises a pump housing having a proximal end, a distal end and a sidewall, the pump housing defining a pharmaceutical agent compartment and an osmotic agent compartment, the pharmaceutical agent compartment being separated from the osmotic agent compartment by a movable piston; a first semipermeable membrane fitted to the proximal end and a second semipermeable membrane fitted to a portion of the sidewall defining the osmotic engine compartment, both the first and second semipermeable membranes being adapted to allow water to cross into the osmotic engine compartment; an impermeable membrane scaling the second semipermeable membrane, and an integrated lancet adapted to breach the impermeable membrane.
The integrated lancet mechanism may be adapted to breach the impermeable membrane upon a manual application of force on the mechanism. A spring may bias a lancet away from the impermeable membrane. The integrated lancet mechanism may include a plurality of through holes, the through holes allowing water into the mechanism and in contact with the second semipermeable membrane when the impermeable membrane is breached. The pharmaceutical agent compartment may be preloaded with a pharmaceutical agent and the pump may be configured to infuse the pharmaceutical agent at a first rate based upon a composition, thickness and surface area of the first semipermeable membrane when the impermeable membrane is intact and may be configured to infuse the pharmaceutical agent at a second infusion rate when the impermeable membrane has been breached. The second rate may be based upon the composition, thickness and surface area of the first and the second semipermeable membranes. The pharmaceutical agent may include Fentanyl, infused within the range of about 10 to about 300 milligrams per day. The pharmaceutical agent may include a combination of Fentanyl and Sufentanil, infused within the range of about 1 to about 25 micrograms per day for Sufentanil and within the range of about 10 to about 30 milligrams per day of Fentanyl. Alternately still, the pharmaceutical agent may include a combination of Sufentanil and Clonidine, infused within a range of about 1 to about 25 micrograms per day for Sufentanil and within a range of about 25 to about 150 micrograms per day for Clonidine.
A method of delivering a pharmaceutical agent, according to a still further embodiment, comprises the steps of implanting an osmotic pump including a first and a second semipermeable membrane, the second impermeable membrane being initially sealed by an impermeable membrane, the pump including an integrated lancet mechanism adapted to breach the impermeable membrane; infusing the pharmaceutical agent at a first infusion rate based upon a composition, thickness and surface area of the first semipermeable membrane; applying force to the lancet mechanism to cause the mechanism to breach the impermeable membrane and expose the initially sealed second semipermeable membrane, and infusing the pharmaceutical agent at a second infusion rate that is higher than the first infusion rate, the second infusion rate being based upon a composition, thickness and surface area of the first and the second semipermeable membranes. The force-applying step may be carried out while the pump is implanted. A further step of palpating the implanted pump to locate the integrated lancet mechanism thereof prior to the force-applying step may also be carried out.
An implantable osmotic pump system, according to another embodiment of the present invention, comprises a pump housing having a proximal end, a distal end and a sidewall, the pump housing defining a pharmaceutical agent compartment and an osmotic agent compartment, the pharmaceutical agent compartment being separated from the osmotic agent compartment by a movable piston; a first semipermeable membrane fitted to a portion of the sidewall defining the osmotic engine compartment, the first semipermeable membrane being adapted to allow water to cross into the osmotic engine compartment and a first sealing member covering and sealing the first semipermeable membrane.
The proximal end of the pump housing may be impermeable to water. The first sealing is member may include a spacer fitted to the sidewall, the spacer including an impermeable membrane that is adapted to be breached by a lancet. The pump housing and the spacer may be configured to allow the spacer to be screwed on the sidewall. The spacer may be fitted to the pump housing by an ultrasonic weld.
The system may further include at least one second semipermeable membrane fitted to the portion of the sidewall defining the osmotic engine compartment, the second semipermeable membrane(s) being adapted to allow water to cross into the osmotic engine compartment; at least one second sealing member covering and sealing a respective one of the at least one second semipermeable membrane. The first and the at least one second sealing members may each include a spacer fitted to the sidewall, the spacer including an impermeable membrane that is adapted to be breached by a lancet. The impermeable membrane may be visible under fluoroscopy. At least the portion of the sidewall defining the osmotic engine compartment may be substantially flat and the pump housing may have a generally rectangular shape with rounded atraumatic edges.